Amantadine and its derivatives with various biological activities have been widely used in the medical field. Rimantadine (1-aminoethyl adamantane) is currently used in medicaments for the prevention and treatment of influenza. Amantadine is widely used in the treatment of influenza and Parkinson's disease (PD) (Schwab et al., J. Am. Med. Assoc. 1969, 208: 1168). Memantine (1,3-dimethyl adamantane) currently is used as the only NMDA receptor antagonist proved by FDA to be used for the treatment of moderate to severe Alzheimer's Disease (AD). The NMDA receptor is an important subtype of excitatory amino acid ionic glutamate receptors in central nervous system, and is also an important receptor related to the learning and memory processes. When the NMDA receptor channel is opened, some cations, such as Ca2+, K+ and Na+ maybe allowed unselectively to enter into the cells, and the entry of such ions, especially calcium ions, may cause a series of biochemical reactions, which may induce neurotoxicity and eventually cause neuronal apoptosis. Memantine is a noncompetitive antagonist of the NMDA receptor open-channel, and it can combine with the binding sites in the ion channel to block the ion flow and thus has neuro-protective effect. The combination of memantine to NMDA receptor is reversible with a moderate rate of dissociation, which may ensure the pharmacological effects and on the other hand may prevent the channel from being blocked for normal physiological functions (Lipton et al., Journal of Neurochemistry 2006, 97: 1611-1626). Meanwhile, memantine has a strong voltage dependence to the antagonism of the NMDA receptor and can bind to the receptor only under neuronal depolarization, and thus can block the activation of the NMDA receptor as neurons being continually polarized in pathological conditions, but does not block the activation of the NMDA receptor in normal physiological conditions (Wenk et al, CNS Drug Reviews 2003, 9 (3): 275-308; McKeage, Drugs & Aging 2010, 27 (2): 177-179). Such protection mechanism also has important significance for the treatment of other disorders of central nervous system, such as stroke, PD and ALS.
Nitric oxide (NO) also has a variety of biological activities in the body, and has a function of signaling molecules. Nitric oxide molecules can penetrate the cell wall into the smooth muscle cells to relax the cells, dilate blood vessels, and lower blood pressure. NO molecules can also enter into platelet cells and reduce their activities, and thus can inhibit the cells' aggregation and adhesion to the vascular endothelium, and further prevent thrombosis and atherosclerosis. Nitric oxide, as a free radical gas with an unpaired electron, is very unstable in the body and can easily react with free radicals, and thus can reduce the number of free radicals. The accumulation of free radicals can cause rupture of nucleic acids, inactivation of enzymes, depolymerization of polysaccharides, and peroxidation of lipids, and eventually may cause the neuronal death (Yan et al Free Radic Biol Med 2013, 62: 90-101). NO has very high activity towards various of radicals, and can effectively reduce the number of free radicals, however, it's synthesis in the body requires nitric oxide synthase (NOS). Under normal conditions, NOS has relatively low activity, and needs to be activated with nitro molecules or saponins. Introduction of a NO releasing group in a small molecule drug, such as in nitroglycerin, may increase NO content in the body, and thus may significantly enhance the therapeutic effect.
As the pathogenesis of AD is rather complex, currently available methods for clinical treatment of AD are very limited; there are only four kinds of acetylcholine esterase inhibitors and one NMDA receptor inhibitor. Such drug molecules with single target function may only relieve some clinical symptoms but cannot actually cure the disease of AD and thus cannot block the neurodegenerative process.